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VITAMIN D DEFICIENCY
Shawn M. Cole, MD and David Podell, MD, PhD
Week 13
Learning Objectives:
1. Recognize the clinical presentations and prevalence of vitamin D deficiency
2. Understand the risk factors and pathophysiology of vitamin D deficiency
3. Appreciate the preventative clinical implications of maintaining adequate vitamin D
levels
4. Learn appropriate treatment strategies for vitamin D deficiency
CASE ONE:
Ms. D. is a 55-year-old African-American woman with a history of hypertension, stage III
chronic kidney disease, and rheumatoid arthritis who presents in your clinic for a followup examination. Six weeks ago she was hospitalized after sustaining a fall which led to a
hip fracture. Her post-operative course has been uneventful, and she is meeting her
rehabilitation goals. Her active complaints include a two-month history of mild fatigue and
increased pain sensitivity described as “body aches everywhere” which feels very different
than her typical RA joint flare-ups. She describes diffuse, constant, achy myalgias with a
severity of 3/10, and without any strength or functional impairment. Patient is compliant
with her medications, which include lisinopril 10mg daily, hydrochlorothiazide 25mg daily,
prednisone 5mg daily, and fish oil supplements. She is up to date on her age appropriate
cancer screening, and all of these studies have been negative throughout her life.
Physical examination reveals a dysphoric, obese lady in no apparent distress.
Musculoskeletal exam is normal with appropriate strength, full range of motion, and the
absence of muscle tenderness on palpation. Her hands have mild chronic RA changes
bilaterally at her MCP joints with no active synovitis. Upon assessing pedal edema, Ms. D.
describes significant tenderness before withdrawing her foot. Depression screen is positive
for mild symptoms which were absent on previous encounters.
Questions:
1. What is the differential diagnosis for this patient’s pain symptoms? Are there
any historical or physical examination clues to narrow your clinical suspicion?
Would you order any laboratory studies at this point and, if so, what would you
order?
The differential diagnosis for this patient’s symptoms is very broad but should
include thyroid dysfunction, hepatitis, viral myositis or myalgia, autoimmune myositis
(poly- or dermato-), HIV, pain related to primary depression, malignancy of bone
(including primary and metastatic), fibromyalgia, myofascial pain syndrome, and, of
course, vitamin D deficiency/osteomalacia, which is a widely underdiagnosed
condition.
Historically, Ms. D. presents with diffuse achy pain, fatigue, and new depressive
symptoms, and withdraws her foot upon pressure application on the dorsum of her
foot to assess for pedal edema. This patient also broke her hip after falling which
supports presumed decreased bone density and may be explained by vitamin D
deficiency, chronic glucocorticoid use or secondary hyperparathyroidism.
Vitamin D deficiency (defined as serum 25-OH vitamin D levels less than 20ng/mL)
often presents in individuals with diffuse achy pain. This phenomenon may be related
to sub-periosteal bone hydration which leads to an expanding and painful effect on
the regional nociceptors.(Holick, MF-Mayo Clin Proc, 2006) This leads to a not
uncommon finding of pain elicitation upon pedal and anterior tibial edema
assessment where pressure overlying a predominantly “bony” area should usually
not cause pain. Another area where this can be assessed is by pressure application
over the sternum (another structure not superimposed by muscle). Pain sensation
during this maneuver should raise suspicion of osteomalacia.
Laboratory studies at this point should include comprehensive metabolic panel,
hepatitis panel, antibodies for HIV, ESR, TSH, and 25-OH vitamin D. It is important
to note that accurate assessment of her vitamin D status can be obtained by
measuring 25-OH vitamin D which serves as the main plasma vitamin D reservoir.
Of note, when she presented with a hip fracture, it would have been prudent to obtain
25-OH vitamin D, PTH, and TSH levels at that time.
CASE ONE CONTINUED:
The blood work comes back a week later and reflects a normal comprehensive metabolic
panel, creatine kinase, hepatitis panel, TSH, ESR, and HIV screen. 25-OH Vitamin D level
is 16ng/mL. Upon further questioning Ms. D., who lives in Massachusetts, admits she is
indoors most of the day, especially in the cold winter months.
2. Describe the risk factors for Vitamin D deficiency. Which risk factors apply to
Ms. D?
The risk factors for vitamin D deficiency are (see Table 2 in NEJM article for
reference):
 Inadequate sunlight exposure: vitamin D is largely synthesized from 7dehydrocholesterol to previtamin D3 in the skin via UV-B radiation
 Increased skin melanin content
 Inadequate dietary intake: it is very difficult to consume adequate vitamin
D in the diet alone, unless excessive fatty fish is consumed
 Seasonal variation especially in higher latitudes: secondary to inadequate
sunlight exposure
 Aging: reduced 7-dehydrocholesterol in the skin (previtamin D3
precursor)
 Malabsorptive conditions: IBD, gastric bypass surgery, celiac disease,
and medications that reduce cholesterol absorption
 Liver failure due to malabsorption: in severe liver disease there is a loss
of vitamin D-25 hydroxylase which is necessary to synthesize 25(OH)vitamin D
 Renal disease: nephrotic syndrome (urinary loss of 25-hydroxy vitamin
D) and chronic kidney disease (decreased 1,25 dihydroxyvitamin D
synthesis)
 Medications: glucocorticoids, HAART medications, anticonvulsants, and
anti-rejection medications may lead to increased catabolism of active
vitamin D forms
 Acquired disorders: several conditions such as hyperthyroidism,
granulamotous disease, primary hyperparathyroidism, and tumor-induced
osteomalacia may lead to reduction of 25-hydroxyvitamin D
 Obesity: vitamin D can be sequestered in body fat, thereby reducing its
availability
This patient clearly has several risk factors, including her skin pigmentation,
inadequate sun exposure and geographical location, chronic kidney disease, age,
obesity, and glucocorticoid use.
3. What are the potential preventative health benefits of treating and correcting
vitamin D deficiency?
Vitamin D deficiency is associated with a vast array of clinical conditions likely
related to the widespread presence of vitamin D receptors in hundreds of cell and
tissue types throughout the body. Cited in the New England Journal of Medicine
review article provided, vitamin D deficiency may be associated with increased
breast, ovarian, pancreatic, and colon cancer risk, along with earlier prostate
cancer development. Individuals from higher latitudes (low sunlight exposure) were
found to have a higher prevalence and worse survival outcomes. Similarly, Crohn’s
disease and multiple sclerosis are more prevalent in higher latitudes which may be
partially attributable to low vitamin D levels. Children born to women with vitamin
D deficiency during pregnancy have an increased chance of developing type-I
diabetes. There is also an association with cardiovascular disease risk including
hypertension and congestive heart failure.
A recent meta-analysis of 18 randomized control trials involving vitamin D
supplementation demonstrated decreased mortality from any cause [RR 0.93 (CI
0.87-0.99)] regardless of concomitant calcium intake. A crucial role for vitamin D
supplementation is in individuals at higher risk for osteoporosis such as this patient
who is post-menopausal, on glucocorticoids, and sustained a fall leading to a hip
fracture. Another meta-analysis showed daily Vitamin D supplementation with 700-
800 IU of cholecalciferol (vitamin D3) was associated with a statistically and
clinically significant decrease in both fall risk and development of fractures
stemming from falls (Bischoff-Ferrari, JAMA, 2005).
The data are inconclusive regarding vitamin D repletion and subsequent pain relief.
A recent study demonstrated repletion of vitamin D levels to normal values may not
relieve diffuse muscular pain symptoms (Warner, J Clin Rheumatol. 2008). There
are limitations to many of these conclusions, however, there appear to be important
clinical implications associated with vitamin D deficiency.
4. What prescription(s) should you give Ms. D to treat her vitamin D deficiency?
Would your approach change if her initial 25-OH Vitamin D levels were
25ng/mL? Should you worry that she may develop vitamin D toxicity if you
treat her too long?
All individuals with vitamin D deficiency or insufficiency should receive vitamin D
repletion along with 1200-1500mg of calcium daily (including dietary calcium
intake). A well established approach to treating this patient’s vitamin D deficiency
would be to start once weekly ergocalciferol (vitamin D2) 50,000 IU for 8-12 weeks
followed by cholecalciferol 1000 IU daily thereafter, although more recent data
suggest that you can use either form for maintenance (Holick, J Clin Endocrinol
Metab, 2008). Treatment should include calcium supplements as well. If risk factors
do not change, she should be treated indefinitely. The target serum 25-OH Vitamin D
level is at least 30ng/mL and should be checked three months following the onset of
treatment.
Vitamin D insufficiency (defined by serum 25-OH vitamin D levels between 2030ng/mL) should be medically treated in the same manner as deficiency.
Vitamin D toxicity is extremely rare with the current treatment recommendations.
One study found that consumption of cholecalciferol 10,000 IU daily for five months
did not cause toxicity. (J Steroid Biochem Mol Biol 2004). Caution should be advised
with vitamin D repletion in individuals with chronic granulomatous conditions, such
as tuberculosis and sarcoidosis, that are sensitive to therapy because of marked
macrophage production of 1,25 dihydroxyvitamin D. Toxicity is largely attributable
to hypercalcemia which may manifest as nausea, vomiting, lethargy, depression,
altered mental status, weakness, and constipation.
CASE ONE CONTINUED:
After treating her for three months, she feels marked improvement in her pain and
depressive symptoms. Follow-up 25-OH Vitamin D value is 34ng/mL.
5. Would you keep treating her?
A reasonable approach to treating her once her 25-OH vitamin D levels normalize
would be maintenance of at least 800IU of Vitamin D3 daily, which is sufficient to
maintain adequate serum vitamin D serum levels (Reinhold, J Steroid Biochem Mol
Biol 2004).
Primary Reference:
1. Holick MF. Vitamin D deficiency. New England Journal of Medicine. 2007;357(3):266281. http://content.nejm.org/cgi/content/full/357/3/266
Additional References:
1. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis
of randomized controlled trials. Archives of Internal Medicine. 2007;167(16):17301737.
2. Bischoff-Ferrari HA, Willett WC, Wong JB. Fracture prevention with vitamin D
supplementation: a meta-analysis of randomized controlled trials. Journal of the
American Medical Association. 2005;293(18):2257-2264.
3. Reinhold V. Why the optimal requirement for Vitamin D3 is probably much higher
than what is officially recommended for adults. J Steroid Biochem Mol Biol 2004;8990:575-9.
4. Holick MF, Biancuzzo RM, Chen TC et al. Vitamin D2 is as effective as vitamin D3
in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin
Endocrinol Metab. 2008;93(3):677-81.
5. Holick MF. High Prevalence of vitamin D inadequacy and implications for health.
Mayo Clin Proc. 2006 Mar;81(3):353-73.
6. Warner AE, Arnspiger, SA. Diffuse musculoskeletal pain is not associated with low
vitamin D levels or improved by treatment with vitamin D. J Clin Rheumatol. 2008
Feb;14(1):12-6.
David Podell completed his internship and residency training at Yale-New Haven Hospital
and completed a fellowship in rheumatology at Yale University School of Medicine. He is
board certified in internal medicine and in the subspecialty of rheumatology.
His special interests include clinical rheumatology and immunology, including fundamental
investigative studies, as well as issues relevant to clinical practice. Other special interests
include initiatives for quality and patient safety.
Dr. Podell attends on the acute medical service at Waterbury Hospital. He is also an
associate with the Comprehensive Center for Arthritis at Waterbury Hospital.
Shawn Cole earned his medical degree from the University of Illinois College of Medicine
and is currently a senior resident in the Yale Primary Care Internal Medicine program.
His clinical interests include musculoskeletal medicine, complementary and alternative
medical therapies, and geriatric healthcare. He plans on practicing in Connecticut upon
completion of his residency.